Module 12: Molecular Tumor Board (MDT) Simulation: Real Patient Cases & Clinical Reporting

1. The Multidisciplinary Molecular Tumor Board (MTB)

The Molecular Tumor Board (MTB) is the multidisciplinary clinical forum where complex comprehensive genomic profiling results are synthesized into personalized patient treatment plans. An effective MTB integrates diverse expertise:

• Medical Oncologist: Evaluates performance status (ECOG), organ function, prior treatment lines, and drug toxicity profiles.
• Molecular Pathologist: Reviews tissue specimen histology, tumor cell purity, necrosis, and assay analytical validity.
• Bioinformatician: Clarifies low-VAF calls, read-level alignments, CNV copy-state certainty, and panel boundaries.
• Clinical Cancer Geneticist: Assesses hereditary cancer risk, advises on incidental germline findings, and guides family testing.

2. Case Study Presentations & Clinical Management Decisions

Case 1: Stage IV Lung Adenocarcinoma

• Genomic Findings: EGFR p.L858R (VAF 35.8%, Tier IA), EGFR p.T790M (Absent, 0%), TP53 p.R273H (VAF 38.2%, Tier IIC), TMB 4.2 mut/Mb (TMB-Low), Microsatellite Stable (MSS).
• MTB Deliberation: EGFR L858R is an activating Tier IA sensitizing driver mutation. TP53 co-mutation is a recognized adverse prognostic biomarker associated with shorter progression-free survival on TKIs. TMB is low; immunotherapy is not indicated.
• Treatment Decision: First-line Osimertinib (3rd-generation CNS-penetrant EGFR TKI) monotherapy (FLAURA regimen). Order plasma cfDNA monitoring at 3-month intervals to monitor for acquired resistance mutations (EGFR C797S or MET amplification).

Case 2: Metastatic Colorectal Cancer (mCRC)

• Genomic Findings: KRAS p.G13D (VAF 61.4%, Tier IA), PIK3CA p.E545K (VAF 18.2%, Tier IIC), BRAF V600E (Wild-Type), MSI Score 2.1% (MSS), TMB 6.8 mut/Mb.
• MTB Deliberation: KRAS G13D is a constitutively activating GTPase driver. Under ASCO/NCCN guidelines, any activating mutation in KRAS exons 2, 3, or 4 confers complete intrinsic resistance to anti-EGFR monoclonal antibodies (Cetuximab and Panitumumab). PIK3CA co-mutation provides an alternative survival pathway.
• Treatment Decision: Contraindication to anti-EGFR therapy. Recommend standard FOLFOX or FOLFIRI plus Bevacizumab (anti-VEGF). Evaluate eligibility for clinical trials combining KRAS pathway and PI3K/mTOR inhibitors upon progression.

Case 3: Infiltrating Ductal Breast Carcinoma

• Genomic Findings: TP53 p.R175H (VAF 44.1%), BRCA1 p.C61G (c.181T>G, VAF 48.2%, Tier IA), ERBB2 (2 copies, Not Amplified), Homologous Recombination Deficiency (HRD) Score 58 (HRD-Positive).
• MTB Deliberation: BRCA1 C61G disrupts the RING finger domain. The high VAF (48.2%) in a tumor-only context strongly suggests an underlying germline pathogenic variant with secondary somatic Loss of Heterozygosity (LOH). High HRD score indicates defective double-strand break repair.
• Treatment Decision:
  1. Immediate Clinical Oncology: Patient is eligible for PARP inhibitors (Olaparib or Talazoparib) and platinum-based chemotherapy.
  2. Genetic Counseling Mandate: Immediate referral to clinical cancer genetics for germline blood testing. If confirmed germline, recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) and cascade predictive testing for first-degree relatives.

3. Standard Architecture of a Clinical Genomic Oncology Report

Every accredited diagnostic genomics report follows a standardized, legally defensible structure:

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                       MOLECULAR ONCOLOGY GENOMIC REPORT
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PATIENT NAME: [Case 1 - Lung]           SPECIMEN ID: FFPE-2026-8841
DATE OF BIRTH: 1964-08-12               TISSUE SITE: Pleural Biopsy
DIAGNOSIS: Stage IV Lung Adenocarcinoma ESTIMATED TUMOR CONTENT: 30%
TEST: Comprehensive Oncology Panel (NGS) SEQUENCING DEPTH: Mean 642x (100% >= 250x)
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1. SUMMARY OF ACTIONABLE SOMATIC ALTERATIONS (TIER I - II)
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Gene       Variant           VAF    Tier   Clinical Actionability / Therapies
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EGFR       p.L858R (Exon 21) 35.8%  Tier IA Sensitive to Osimertinib (First-line NCCN)
TP53       p.R273H (Exon 8)  38.2%  Tier IIC Prognostic; co-mutational resistance marker
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2. PAN-CANCER IMMUNOTHERAPY BIOMARKERS
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- Microsatellite Status:  MSS (Microsatellite Stable, 0.4% unstable loci)
- Tumor Mutational Burden: 4.2 mutations/Mb (TMB-Low, < 10 mut/Mb)
Interpretation: Immunotherapy alone is not indicated based on TMB/MSI status.
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3. ASSAY METHODOLOGY & LIMITATIONS
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Targeted hybrid capture NGS performed on Illumina NextSeq. Limits of detection:
SNVs/Indels >= 5% VAF in specimens with >= 20% tumor purity. This assay was
performed on tumor tissue without matched normal control; constitutional germline
status cannot be definitively established from this test alone.
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